Genetic Predisposition to Low-Density Lipoprotein Cholesterol and Incident Type 2 Diabetes

Area of Science:

• Cardiovascular Genetics
• Metabolic Disease Epidemiology

Background:

• Lowering low-density lipoprotein cholesterol (LDL-C) reduces coronary artery disease (CAD) risk but may increase type 2 diabetes (T2D) risk.
• The genetic underpinnings of the association between cholesterol levels and T2D risk are not fully understood.

Purpose of the Study:

• To investigate the association between genetic predisposition to elevated LDL-C and the risk of incident T2D.
• To explore how genetic variations affecting LDL-C levels influence T2D and CAD risk.

Main Methods:

• A prospective, population-based cohort study using UK Biobank data, including whole-exome sequencing and genotyping.
• Participants were categorized based on familial hypercholesterolemia (FH), predicted loss-of-function (pLOF) variants in APOB or PCSK9, and LDL-C polygenic risk score (PRS) quintiles.
• Cox proportional hazards regression models were used to assess associations between genetic LDL-C factors and incident T2D/CAD, adjusting for relevant covariates.

Main Results:

• Among 361,082 participants, genetic predisposition to lower LDL-C (e.g., FH, pLOF variants) showed varied associations with T2D risk.
• The highest T2D risk was observed in the pLOF group (HR, 1.48), while the FH group had a reduced risk (HR, 0.65).
• An inverse association was found between LDL-C PRS and T2D risk; very high LDL-C PRS was associated with lower T2D risk (HR, 0.72), whereas very low LDL-C PRS was associated with higher risk (HR, 1.26). CAD risk increased with higher LDL-C PRS.

Conclusions:

• Genetic factors influencing LDL-C levels demonstrate an inverse association with T2D risk, suggesting a complex genetic interplay.
• Mechanisms underlying the increased T2D risk associated with genetically determined lower LDL-C warrant further investigation.